PROJECT SUMMARY/ABSTRACT Cocaine abuse, for which there are no FDA-approved pharmacological treatments, is associated with long- term neurobiological and functional alterations underlying decreased affect/motivation, impaired decision- making, sleep disturbances, and an exaggerated response to cocaine-related cues that are associated with high rates of relapse. Human imaging studies report a state of ?hypofrontality? (e.g. reduced blood oxygen level dependent [BOLD] activation in the prefrontal cortex [PFC] in response to cognitive challenge), yet increased response (e.g. increased BOLD response) to cocaine-related cues in abstinent cocaine users. Preclinical studies provide evidence that altered mesocorticostriatal glutamatergic (Glu) signaling underlies some of these changes. For example, increased glutamate-mediated synaptic plasticity in the PFC, NAc and ventral tegmental area (VTA) are present following extended cocaine self-administration (SA). Exposure to cocaine- related cues increases Glu (via cortico-accumbal) and DA concentrations (via cortico-VTA driven DA release) in the NAc and attenuating these enhanced responses in the NAc represents a promising avenue for relapse prevention. Inhibiting Glu function via negative allosteric modulation (NAM) of the metabotropic glutamate (mGlu) receptor subtype, mGlu5 attenuates cocaine self-administration (SA) and cue-induced reinstatement of cocaine-seeking behavior in rodents and nonhuman primates. The overall goals of the proposed studies are to 1) understand functional and neurochemical changes in the PFC and NAc in awake rats at rest and in response to cocaine-related cues during abstinence following a cocaine self-administration (SA) regimen that models compulsive drug use (6-h long access SA); and 2) test the hypothesis that inhibition of glutamatergic function via mglu5 NAMs will attenuate the behavioral, functional and neurochemical response to cocaine- paired conditioned cues that contribute to relapse. The proposed studies will systematically assess functional and neurochemical changes in the cortico-accumbal circuit related to cue-induced reinstatement (preclinical model of relapse), by utilizing fMRI and microdialysis techniques in awake rats. The studies proposed during the K99 phase of the application will examine the effects of the full mGlu5 NAM VU0409106 on cue-induced reinstatement, cue-induced changes in BOLD response (Aim 1) and on cue- induced changes in Glu and DA concentrations in the PFC and NAc using microdialysis (Aim 2). These studies will provide the applicant with the expertise to independently establish and conduct awake fMRI and microdialysis studies in awake rats. In the studies proposed in Aims 3 and 4 (R00 portion) the applicant will test the hypothesis that newly developed and characterized partial mGlu5 NAMs, compared to full mGlu5 NAMs, will be equally effective in attenuating cue-induced reinstatement and the underlying neurochemical and functional correlates in the PFC and NAc, yet will exhibit a broader therapeutic window. The therapeutic index of full mGlu5 NAMs is limited by adverse side effects, including cognitive impairments and psychotomimetic-like effects. Partial mGlu5 NAMs, represented by M-5MPEP, attenuated cocaine SA and discrimination within a dose range that also produced antidepressant- and anxiolytic-like effects, but in contrast to full mGlu5 NAMs did not induce sedation or potentiate PCP-induced hyperlocomotion. We will examine effects of the partial and full mGlu5 NAMs M-5MPEP and VU0409106 on measures of attention, working memory, arousal and sleep, indices of cocaine-induced disorders during abstinence, to examine broader therapeutic potential or adverse effects. Development of partial mGlu5 NAMs represents an unprecedented opportunity to investigate the ability of these ligands to mitigate multiple behavioral components that are associated with cocaine relapse. Furthermore, these studies directly align with NIDA's mission to conduct translational research examining environmental factors that influence the neurobiological mechanisms contributing to addictive behaviors and exploring novel pharmacological treatment approaches. As recently highlighted by Dr. Volkow and colleagues, developing translational biomarkers that can identify disease symptomatology, trajectory or treatment response is integral for developing treatments for relapse prevention (ACS Chem Neurosci 2015). The proposed studies integrate two such translational measures of CNS function. The proposed studies align with the long-term goals of the applicant in developing a successful independent research laboratory integrating highly translational behavioral and functional assessments with the skill set to understand underlying circuitry and neurochemistry. The outcome of these studies will undoubtedly provide compelling support for multiple avenues of research directly pursuing cocaine addiction studies and provide the foundation for researching neuropsychiatric disorders comorbid with addiction. The research and development plan outlines a cohesive strategy to meet these long-term goals as well as the short-term goals of training in functional imaging and to strengthen the neuroscience background for the applicant, to complement the strong behavioral pharmacology background and established EEG methodology. The collaborative nature and extensive expertise across multiple areas spanning chemical synthesis, in vitro and in vivo assessments, drug discovery efforts and clinical collaborations provides an enriching environment to develop a well-rounded principle investigator with the skills to run a highly productive and innovative independent research laboratory.